Three major classes of adenosine receptors, classified as A.sub.1, A.sub.2, and A.sub.3, have been characterized pharmacologically and have been defined on the basis of cloned sequences.sup.1-4. A.sub.1 receptors are coupled to the inhibition of adenylate cyclase through G.sub.i proteins and have also been shown to couple to other secondary messenger systems, including inhibition or stimulation of phosphoinositol turnover and activation of ion channels. A.sub.2 receptors are further divided into two subtypes, A.sub.2A and A.sub.2B, at which adenosine agonists activate adenylate cyclase with high and low affinity, respectively. The A.sub.3 receptor sequence was first identified in a rat testes cDNA library, and this sequence, later cloned by homology to other G-protein coupled receptors from a rat brain cDNA library, was shown to correspond to a novel, functional adenosine receptor.
Many selective agonists and antagonists have been developed for the A.sub.1.sup.10-15 and A.sub.2a.sup.16-19 receptor subtypes. Some of these have shown promise as potential therapeutic agents in the treatment of hypertension.sup.17, Parkinson's disease.sup.20, cognitive deficits.sup.21, schizophrenia.sup.22, epilepsy and renal failure.sup.23. Selective and/or high affinity agonists and antagonists for the A.sub.2b receptor are not well known.
The discovery of the A.sub.3 receptor has opened new therapeutic vistas in the purine field. In particular, the A.sub.3 receptor mediates processes of inflammation, hypotension, and mast cell degranulation. This receptor apparently also has a role in the central nervous system. The A.sub.3 selective agonist IB-MECA induces behavioral depression and upon chronic administration protects against cerebral ischemia. A.sub.3 selective agonists at high concentrations were also found to induce apoptosis in HL-60 human leukemia cells. These and other findings have made the A.sub.3 receptor a promising therapeutic target. Selective antagonists for the A.sub.3 receptor are sought as potential antiinflammatory or possibly antiischemic agents in the brain. Recently, A.sub.3 antagonists have been under development as antiasthmatic, antidepressant, antiarrhythmic, renal protective, antiparkinson and cognitive enhancing drugs.
Selective agonist.sup.24 and antagonist.sup.25-28 ligands have been developed for the A.sub.3 receptor. In the agonist field, 1B-MECA (N.sup.6 -(3-iodobenzyl)adenosine-5'-methyluronamide) shows a Ki value of 1.1 nM at rat A.sub.3 receptors and a 50-fold selectivity versus either A.sub.1 or A2a receptors.sup.29. The related agonist, [125I]AB-MECA (N.sup.6 -(4-amino-3-iodobenzyl)adenosine-5'-methyluronamide).sup.30 has become a useful radioligand for the screening of new derivatives at cloned A.sub.3 receptors.
More recently, N.sup.6 -(substituted phenylcarbamoyl)adenosine-5'-uronamides, where the substituent is 2-chloro, 3-chloro or 4-methoxy, have been prepared (Baraldi et al., Advance ACS Abstracts, Dec. 15, 1995) and demonstrated affinity at A.sub.3 receptors in the low nanomolar range (Ki values less than 10 nm). However, other closely related substituents, such as 3-bromo, showed a ten-fold loss in activity and affinity for the A.sub.3 receptor (Baraldi et al., J. Med Chem., 39:802-806 (1996). Further, while the 2-chloro, 3-chloro and 4-methoxy substituents showed high affinity for the A.sub.3 receptor and high selectivity relative to the A.sub.2 receptor, the selectivity for the A.sub.1 receptor was not as high (the ratio of A.sub.3 to A.sub.1 activity was between 4 and 15).
A number of A.sub.3 adenosine receptor agonists which have been previously synthesized are structurally related to adenosine itself, in which the ribose moiety is mainly intact. On the ribose, 5'-alkyluronamide groups are generally tolerated. Positions on the structure of adenosine providing flexibility of substitution, in general for adenosine agonists, have been the N.sup.6 and C.sub.2 position. At the N.sup.6 position, most alkyl or aryl derivatives are A.sub.1 selective. At the C.sub.2 position, many C-, N-, or O-derivatives are A.sub.2a selective. Benzyl derivatives at the N.sup.6 position have been shown to be A.sub.3 selective.
It would be advantageous to provide other modulators of the A.sub.1 and A.sub.3 receptors, with high affinity and selectivity for these receptors with respect to the other adenosine receptors.
It is therefore an object of the present invention to provide compounds and methods of preparation and use thereof, which are agonists or partial agonists of the adenosine receptors, in particular, the adenosine A.sub.1 and A.sub.3 receptors.